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Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmel syndrome.

Cano-Gauci DF, Song HH, Yang H, McKerlie C, Choo B, Shi W, Pullano R, Piscione TD, Grisaru S, Soon S, Sedlackova L, Tanswell AK, Mak TW, Yeger H, Lockwood GA, Rosenblum ND, Filmus J - J. Cell Biol. (1999)

Bottom Line: These patients display pre- and postnatal overgrowth, and a varying range of dysmorphisms.Since BWS has been associated with biallelic expression of insulin-like growth factor II (IGF-II), it has been proposed that GPC3 is a negative regulator of IGF-II.In the particular case of the kidney, we demonstrate that there is an early and persistent developmental abnormality of the ureteric bud/collecting system due to increased proliferation of cells in this tissue element.

View Article: PubMed Central - PubMed

Affiliation: The Ontario Cancer Institute, Toronto, Ontario, M5G 2M9 Canada.

ABSTRACT
Glypicans are a family of heparan sulfate proteoglycans that are linked to the cell surface through a glycosyl-phosphatidylinositol anchor. One member of this family, glypican-3 (Gpc3), is mutated in patients with the Simpson-Golabi-Behmel syndrome (SGBS). These patients display pre- and postnatal overgrowth, and a varying range of dysmorphisms. The clinical features of SGBS are very similar to the more extensively studied Beckwith-Wiedemann syndrome (BWS). Since BWS has been associated with biallelic expression of insulin-like growth factor II (IGF-II), it has been proposed that GPC3 is a negative regulator of IGF-II. However, there is still no biochemical evidence indicating that GPC3 plays such a role.Here, we report that GPC3-deficient mice exhibit several of the clinical features observed in SGBS patients, including developmental overgrowth, perinatal death, cystic and dyplastic kidneys, and abnormal lung development. A proportion of the mutant mice also display mandibular hypoplasia and an imperforate vagina. In the particular case of the kidney, we demonstrate that there is an early and persistent developmental abnormality of the ureteric bud/collecting system due to increased proliferation of cells in this tissue element. The degree of developmental overgrowth of the GPC3-deficient mice is similar to that of mice deficient in IGF receptor type 2 (IGF2R), a well characterized negative regulator of IGF-II. Unlike the IGF2R-deficient mice, however, the levels of IGF-II in GPC3 knockouts are similar to those of the normal littermates.

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Analysis of cell proliferation in the renal collecting system of the GPC3-deficient mice. Incorporation of BrdU into cells of the ureteric buds or collecting ducts, identified by fluorescein-conjugated DBA, was detected in tissue sections of embryonic kidneys using an anti-BrdU peroxidase-conjugated antibody. (A) Bright-field (BF) and fluorescence (IF) images of representative kidney sections from Gpc3 +/+ and Gpc3 −/ mice at E12.5 and E16.5. The arrows mark the position of typical ureteric buds or collecting ducts, identified by fluorescein-DBA. BrdU-labeled cells (brown) are present in both the collecting system and in tissue elements derived from the metanephric blastema, and are more numerous in the cells of the collecting system of the Gpc3 −/ mice. Bar, 18.7 μm (400×). (B) Quantification of cell proliferation in the ureteric buds or collecting ducts in the kidneys of Gpc3 +/+ and Gpc3 −/ mice at E12.5, E13.5, and E16.5. Percent proliferation was calculated as the ratio of BrdU-labeled cells to the total number of ureteric bud or collecting duct cells analyzed. Bars represent the mean + SEM.
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Figure 8: Analysis of cell proliferation in the renal collecting system of the GPC3-deficient mice. Incorporation of BrdU into cells of the ureteric buds or collecting ducts, identified by fluorescein-conjugated DBA, was detected in tissue sections of embryonic kidneys using an anti-BrdU peroxidase-conjugated antibody. (A) Bright-field (BF) and fluorescence (IF) images of representative kidney sections from Gpc3 +/+ and Gpc3 −/ mice at E12.5 and E16.5. The arrows mark the position of typical ureteric buds or collecting ducts, identified by fluorescein-DBA. BrdU-labeled cells (brown) are present in both the collecting system and in tissue elements derived from the metanephric blastema, and are more numerous in the cells of the collecting system of the Gpc3 −/ mice. Bar, 18.7 μm (400×). (B) Quantification of cell proliferation in the ureteric buds or collecting ducts in the kidneys of Gpc3 +/+ and Gpc3 −/ mice at E12.5, E13.5, and E16.5. Percent proliferation was calculated as the ratio of BrdU-labeled cells to the total number of ureteric bud or collecting duct cells analyzed. Bars represent the mean + SEM.

Mentions: We hypothesized that a disregulation of cell proliferation might underlie the accelerated ureteric bud development observed in Gpc3 −/ kidneys. Thus, cell proliferation in the ureteric buds/collecting ducts was assessed by measuring BrdU incorporation into DNA. Quantification of BrdU uptake in four sets of wild-type and Gpc3 −/ mice at E12.5 demonstrated a 2.8-fold increase in the percentage of cells that incorporated BrdU in the epithelial cells of the collecting system, identified by DBA binding (Fig. 8 A). This enhancement of BrdU uptake in the collecting system persisted at E13.5 (2.6-fold increase) and E16.5 (3.4-fold increase). In contrast, while the basal rate of cell proliferation was generally high in mesenchymal cells adjacent to the collecting system (identified by morphology and lack of staining with DBA), there was no significant difference in mesenchymal cell proliferation in the kidneys of Gpc3 +/+ versus Gpc3 −/ mice at E 12.5 (27.6 ± 3.0% versus 30.0 ± 1.7%), E13.5 (18.7 ± 3.0% versus 24.0 ± 1.7%), or E16.5 (21.2 ± 2.7% versus 24.3 ± 6.4%; four independent samples, 250 mesenchymal cells counted per sample).


Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmel syndrome.

Cano-Gauci DF, Song HH, Yang H, McKerlie C, Choo B, Shi W, Pullano R, Piscione TD, Grisaru S, Soon S, Sedlackova L, Tanswell AK, Mak TW, Yeger H, Lockwood GA, Rosenblum ND, Filmus J - J. Cell Biol. (1999)

Analysis of cell proliferation in the renal collecting system of the GPC3-deficient mice. Incorporation of BrdU into cells of the ureteric buds or collecting ducts, identified by fluorescein-conjugated DBA, was detected in tissue sections of embryonic kidneys using an anti-BrdU peroxidase-conjugated antibody. (A) Bright-field (BF) and fluorescence (IF) images of representative kidney sections from Gpc3 +/+ and Gpc3 −/ mice at E12.5 and E16.5. The arrows mark the position of typical ureteric buds or collecting ducts, identified by fluorescein-DBA. BrdU-labeled cells (brown) are present in both the collecting system and in tissue elements derived from the metanephric blastema, and are more numerous in the cells of the collecting system of the Gpc3 −/ mice. Bar, 18.7 μm (400×). (B) Quantification of cell proliferation in the ureteric buds or collecting ducts in the kidneys of Gpc3 +/+ and Gpc3 −/ mice at E12.5, E13.5, and E16.5. Percent proliferation was calculated as the ratio of BrdU-labeled cells to the total number of ureteric bud or collecting duct cells analyzed. Bars represent the mean + SEM.
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Related In: Results  -  Collection

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Figure 8: Analysis of cell proliferation in the renal collecting system of the GPC3-deficient mice. Incorporation of BrdU into cells of the ureteric buds or collecting ducts, identified by fluorescein-conjugated DBA, was detected in tissue sections of embryonic kidneys using an anti-BrdU peroxidase-conjugated antibody. (A) Bright-field (BF) and fluorescence (IF) images of representative kidney sections from Gpc3 +/+ and Gpc3 −/ mice at E12.5 and E16.5. The arrows mark the position of typical ureteric buds or collecting ducts, identified by fluorescein-DBA. BrdU-labeled cells (brown) are present in both the collecting system and in tissue elements derived from the metanephric blastema, and are more numerous in the cells of the collecting system of the Gpc3 −/ mice. Bar, 18.7 μm (400×). (B) Quantification of cell proliferation in the ureteric buds or collecting ducts in the kidneys of Gpc3 +/+ and Gpc3 −/ mice at E12.5, E13.5, and E16.5. Percent proliferation was calculated as the ratio of BrdU-labeled cells to the total number of ureteric bud or collecting duct cells analyzed. Bars represent the mean + SEM.
Mentions: We hypothesized that a disregulation of cell proliferation might underlie the accelerated ureteric bud development observed in Gpc3 −/ kidneys. Thus, cell proliferation in the ureteric buds/collecting ducts was assessed by measuring BrdU incorporation into DNA. Quantification of BrdU uptake in four sets of wild-type and Gpc3 −/ mice at E12.5 demonstrated a 2.8-fold increase in the percentage of cells that incorporated BrdU in the epithelial cells of the collecting system, identified by DBA binding (Fig. 8 A). This enhancement of BrdU uptake in the collecting system persisted at E13.5 (2.6-fold increase) and E16.5 (3.4-fold increase). In contrast, while the basal rate of cell proliferation was generally high in mesenchymal cells adjacent to the collecting system (identified by morphology and lack of staining with DBA), there was no significant difference in mesenchymal cell proliferation in the kidneys of Gpc3 +/+ versus Gpc3 −/ mice at E 12.5 (27.6 ± 3.0% versus 30.0 ± 1.7%), E13.5 (18.7 ± 3.0% versus 24.0 ± 1.7%), or E16.5 (21.2 ± 2.7% versus 24.3 ± 6.4%; four independent samples, 250 mesenchymal cells counted per sample).

Bottom Line: These patients display pre- and postnatal overgrowth, and a varying range of dysmorphisms.Since BWS has been associated with biallelic expression of insulin-like growth factor II (IGF-II), it has been proposed that GPC3 is a negative regulator of IGF-II.In the particular case of the kidney, we demonstrate that there is an early and persistent developmental abnormality of the ureteric bud/collecting system due to increased proliferation of cells in this tissue element.

View Article: PubMed Central - PubMed

Affiliation: The Ontario Cancer Institute, Toronto, Ontario, M5G 2M9 Canada.

ABSTRACT
Glypicans are a family of heparan sulfate proteoglycans that are linked to the cell surface through a glycosyl-phosphatidylinositol anchor. One member of this family, glypican-3 (Gpc3), is mutated in patients with the Simpson-Golabi-Behmel syndrome (SGBS). These patients display pre- and postnatal overgrowth, and a varying range of dysmorphisms. The clinical features of SGBS are very similar to the more extensively studied Beckwith-Wiedemann syndrome (BWS). Since BWS has been associated with biallelic expression of insulin-like growth factor II (IGF-II), it has been proposed that GPC3 is a negative regulator of IGF-II. However, there is still no biochemical evidence indicating that GPC3 plays such a role.Here, we report that GPC3-deficient mice exhibit several of the clinical features observed in SGBS patients, including developmental overgrowth, perinatal death, cystic and dyplastic kidneys, and abnormal lung development. A proportion of the mutant mice also display mandibular hypoplasia and an imperforate vagina. In the particular case of the kidney, we demonstrate that there is an early and persistent developmental abnormality of the ureteric bud/collecting system due to increased proliferation of cells in this tissue element. The degree of developmental overgrowth of the GPC3-deficient mice is similar to that of mice deficient in IGF receptor type 2 (IGF2R), a well characterized negative regulator of IGF-II. Unlike the IGF2R-deficient mice, however, the levels of IGF-II in GPC3 knockouts are similar to those of the normal littermates.

Show MeSH
Related in: MedlinePlus